title: Minimalist hybrid ligand/receptor-based pharmacophore model for CXCR4 applied to a small-library of marine natural products led to the identification of phidianidine a as a new CXCR4 ligand exhibiting antagonist activity.
abstract: Here, we present a minimal hybrid ligand/receptor-based pharmacophore model (PM) for CXCR4, a chemokine receptor deeply involved in several pathologies, such as HIV infection, rheumatoid arthritis, cancer development/progression, and metastasization. This model, considerably simpler than those thus far proposed for this receptor, has been used to search for new CXCR4 inhibitors in a small marine natural product library available at ICB-CNR Institute (Pozzuoli, NA, Italy), since natural products, with their naturally selected chemical and functional diversity, represent a rich source of bioactive scaffolds; computational approaches allow searching for new scaffolds with a minimal waste of possibly precious natural product samples; and our "stripped-down" model substantially increases the probabilities of identifying potential hits even in small-sized libraries. This search, also validated by a systematic virtual screening of the same library, has led to the identification of a new CXCR4 ligand, phidianidine A (PHIA). Docking studies supported PHIA activity and suggested its possible binding modes to CXCR4. Using the CXCR4-expressing/CXCR7-negative GH4C1 cell line we show that PHIA inhibits CXCL12-induced DNA synthesis, cell migration, and ERK1/2 activation. The specificity of these effects was confirmed by the lack of PHIA activity in GH4C1 cells, in which siRNA highly reduces CXCR4 expression and the lack of cytoxicity of PHIA was also verified. Thus, PHIA represents a promising lead for a new family of CXCR4 modulators with wide margins of improvement in potency and specificity offered by the small and very simple underlying PM.
authors.affiliation: Institute of Biomolecular Chemistry (ICB) of the National Research Council (CNR) , Via Campi Flegrei 34, 80078 Pozzuoli, Napoli, Italy.
authors.forename: Rosa Maria
authors.initials: RM
authors.lastname: Vitale
authors.forename: Monica
authors.initials: M
authors.lastname: Gatti
authors.forename: Marianna
authors.initials: M
authors.lastname: Carbone
authors.forename: Federica
authors.initials: F
authors.lastname: Barbieri
authors.forename: Vera
authors.initials: V
authors.lastname: Felicità
authors.forename: Margherita
authors.initials: M
authors.lastname: Gavagnin
authors.forename: Tullio
authors.initials: T
authors.lastname: Florio
authors.forename: Pietro
authors.initials: P
authors.lastname: Amodeo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D001665:Binding Sites; D001688:Biological Products / Q000737:chemistry*; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000494:pharmacology; D015870:Gene Expression; D057166:High-Throughput Screening Assays; D006801:Humans; D026121:Indole Alkaloids / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D008024:Ligands; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D062105:Molecular Docking Simulation; D008974:Mollusca / Q000737:chemistry; D010069:Oxadiazoles / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D054387:Receptors, CXCR / Q000172:deficiency / Q000235:genetics; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry*; D014584:User-Computer Interface
chemical_list: C501896:ACKR3 protein, human; D000970:Antineoplastic Agents; D001688:Biological Products; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D026121:Indole Alkaloids; D008024:Ligands; D010069:Oxadiazoles; D034741:RNA, Small Interfering; D054387:Receptors, CXCR; D019718:Receptors, CXCR4; D054852:Small Molecule Libraries; C559224:phidianidine A; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3